Advances in chronic myelomonocytic leukemia and future prospects: Lessons learned from precision genomics

Abstract

In the latest World Health Organization classification of myeloid neoplasms, chronic myelomonocytic leukemia (CMML) exists as a separate entity under the category of myelodysplastic/myeloproliferative (MDS/MPN) overlap syndromes. Outcomes remain uniformly poor with a median overall survival of ~2 years and an inherent risk of transformation into acute myeloid leukemia (15%-20% over 5 years). Due to unique biologic characteristics such as overlapping features of myelodysplasia and myeloproliferation, and clinical diversity despite relative genomic homogeneity, CMML represents a unique model to study chronic myeloid tumor biology. Recent advances have focused on understanding the role of putative genomic abnormalities, in particular, clonal evolution of pathogenic alterations in genes regulating the epigenome (TET2), chromatin architecture (ASXL1), spliceosome complex (SRSF2, SF3B1), and cell signaling (NRAS, KRAS, CBL, JAK2). Disease prognostication has evolved from purely clinical prognostic models to those incorporating pathogenic gene variants. Therapeutic options in this disease remain dismal with only two agents approved by the United States Food and Drug Administration, namely 5-azacitidine and decitabine. Allogeneic hematopoietic stem cell transplantation remains the sole curative option in this disease; however, is associated with substantial treatment-related morbidity and mortality. Future areas of research include opportunities to further improve disease prognostication by employing novel technologies such as machine learning, incorporation of methylation and cytokine signatures, in addition to gene mutations; insights into clonal origins of this disease, and novel therapeutic strategies.